Korean Motherisk
한정열 MD,PhD
Education course : Testing stratiges for BioPharmaceuticals
E-1 : Introduction into BioPharmaceuticals and DART
M. Beekhui...
Definition biopharmaceuticals
Biotechnology-derived pharmaceuticals
 A scientific-based case-by-case approach is
considered the most appropriate for nonclinical
safety assessment of biophar...
8. Sept
Why test vaccines for developmental toxicity?
– possible specific risks to reproduction
8. Sept
Goal :
To enhance the ability of course participants to approach NHP
DART study design and implementation in an ef...
9. Sept.
ETS presidents Award Lecture
: A Ornoy, Israel
Diabetic embryopathy: from clinical to molecular studies in
experi...
Symphosium 1:
Developmental toxicity of nanoparticles-effects, issues and directions
for future research
S1-0 : Introducti...
S1-1: Prenatal exposure to nanoparticles effects and potential
mechanisms
Differ compared to that of bulk materials
Interf...
S1-2: Nanoparticles and early human placenta – sophisticated
Matter meets Sophistigated Tissues
Pharmaceutical industry
Co...
9. Sept.ETS/TS Exchange lecture : Myth or Merit : The
use of a second species in Developmental
Toxicity Testing
ETS subtit...
9. Sept.
TS subtitle : Screening environmental agents
1960 thalidomide disaster : rodent & non-rodent toxicity testing
Rel...
9. Sept.
Symphosium 2:
Cross industry data survey of the value of rabbit developmental toxicity
data in the risk of assess...
10. Sept.
Symposium 3 : Reproductive toxicity –endocrine mechanisms
S3-1: Identification and assessment of endocrine disru...
10. Sept.
Symposium 3 : Reproductive toxicity –endocrine mechanisms
S3-1: Identification and assessment of endocrine disru...
10. Sept.
Symposium 4 : Reproductive toxicity- epigenetics
S4-1: System and genome wide adaptation of the epigenome
to ges...
10. Sept.
S4-2: Sex-specific transcriptional and epigenetic signatures associated
with peripheral leptin-resitance
 Non-c...
10. Sept.
S4-3: Diabetic embryopathy : the role of epigenetics
 Epigenetic information : silencing or activation of genes...
11. Sept.
Symposium 5 : Regulatory acceptance of alternative/in vitro methods
S5-1: Bottlenecks for the implementation of ...
Abstract
Characterization of phosphatidylethanol blood concentrations
for screening alcohol consumption in early pregnancy...
Abstract
Effects of ß-carotene in cultured mouse embryos exposed to nicotine
Cunmei Lin, Sang-Yoon Nam Chung-buk natioanal...
Diet and Autism spectrum disorders(ASD)
Yasmin H.
Departmenet of Human nutrition, The University of Alabama, USA
No clear ...
Synergistic use of ex vivo and in vitro placenta model
systems to study various aspects of nanomaterial
behavior at the pl...
 Biopharmaceuticals & DART
 Nanoparticles
 2nd species of developmental toxicity
 Endocrine disruptor
 Epigenetics
 ...
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
41st annual meeting of the european teratology society
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41st annual meeting of the european teratology society

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41차 유럽기형학회 보고

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41st annual meeting of the european teratology society

  1. 1. Korean Motherisk 한정열 MD,PhD
  2. 2. Education course : Testing stratiges for BioPharmaceuticals E-1 : Introduction into BioPharmaceuticals and DART M. Beekhuizen, Netherland 8. Sept Aim : Overview of stepwise approach to follow on preclinical DART testing for biopharmaceuticals
  3. 3. Definition biopharmaceuticals Biotechnology-derived pharmaceuticals
  4. 4.  A scientific-based case-by-case approach is considered the most appropriate for nonclinical safety assessment of biopharmaceuticals.  There is not one standard approach applicable per biopharmaceutical subclass  The stepwise approach is similar for general toxicity as for DART, however DART specifics need to be considered Conclusions :
  5. 5. 8. Sept Why test vaccines for developmental toxicity? – possible specific risks to reproduction
  6. 6. 8. Sept Goal : To enhance the ability of course participants to approach NHP DART study design and implementation in an effective, case-by- case manner.
  7. 7. 9. Sept. ETS presidents Award Lecture : A Ornoy, Israel Diabetic embryopathy: from clinical to molecular studies in experimental animals and man – some historical perspectives Before discovery of insulin : 1921 Severe fertility problem, Sp. Abortions, fetal death Slight neurobehavioral development problems( mainly inattention, slight gross and fine motor delay) : PGDM, GDM hyperglycemia, embryonic malnutrition, oxidative stress maternal diabetes induced change in embryonic gene expression (heart, CNS, and gene related to oxidative stress and hypoxia) Diabetic embryopathy and fettopathy etiologies : embryonic metabolic/nutritional/endocrine disturbance/hypoxia/epigenetic changes
  8. 8. Symphosium 1: Developmental toxicity of nanoparticles-effects, issues and directions for future research S1-0 : Introduction: Light and Ultrastructural Morphology and Permeability of placenta barrier nanoparticles : one of most challenge research target in toxicology nanoparticles : 1-100nm dimension accumulate cellular organelles , damage to cellular cytoplasm capacity to placental barrier , pass to embryonic/fetal tissue and organ <100nm – go to cell by passing cellular membrane <40nm – go to cellular nuclei <35nm – go to brain by passing BBB - so, brain is target Placenta barrier : very strong like BBB ( coherent endothelium, basement membrane, surrounded by syncythiotrophoblast cells with tight epitheliag junctions) 9. Sept.
  9. 9. S1-1: Prenatal exposure to nanoparticles effects and potential mechanisms Differ compared to that of bulk materials Interfere with intrauterine development Effects of gene expression, function of CNS system, immune system, and male reproductive system. Generate oxidative stress and inflammation Interfere placental vasculization Lung inflammation- mediators cross placenta – interfere fetal development For study - particle size, chemistry, surface area, route of exposure 9. Sept.
  10. 10. S1-2: Nanoparticles and early human placenta – sophisticated Matter meets Sophistigated Tissues Pharmaceutical industry Concern due to size Identification of “nano-thalidomid before marketing S1-3: Knocking at the door of the unborn child: issues in developmental and placental nanotoxicology and direction for the future research a variety applications Concern - 18nm particle were transferred to embryos 24 hr after IV Nanotoxicology 3 principles 1. nanomaterial uptake 2. surface effects 3. material properties Basis for understanding of specific reaction & interactions between nanoparticles and transplacental transfer 9. Sept.
  11. 11. 9. Sept.ETS/TS Exchange lecture : Myth or Merit : The use of a second species in Developmental Toxicity Testing ETS subtitles : More safe drugs by less in vivo testing? Issue & limitation are highlighted Small molecule pharmaceuticals: tested in rats and rabbits for toxicity of embryo in 1960 following thalidomide tragedy Two species has sufficient power False positive : discontinuation valuable drugs & limit full potential use So, Q? New paradigm need Evidence based holistic hazard identification & risk assessment together with less traditional animal testing for more safe drug
  12. 12. 9. Sept. TS subtitle : Screening environmental agents 1960 thalidomide disaster : rodent & non-rodent toxicity testing Reliable information on developmental hazard and dose response Not yet norm: genomic metabolomics/proteomic profilling/in vitro predictive models(eq. whole embryo culture, embryonic stem cells)/testing non-mammalian species (eq. Zebra fish) More common approach : laboratory animal test ( rat and rabbit) Q of Rat vs Rabbit – neither species is predictive of risk to human More thoughtful, directed, chemical specific approach is needed
  13. 13. 9. Sept. Symphosium 2: Cross industry data survey of the value of rabbit developmental toxicity data in the risk of assessment for pharmaceutics --- used as the 2nd species of developmental toxicity S2-1: ICH origins of the “2nd species” project UK S2-2: Scientific background S2-3: Emerging data S2-4: Industry perspective S2-5: Regulatory perspective
  14. 14. 10. Sept. Symposium 3 : Reproductive toxicity –endocrine mechanisms S3-1: Identification and assessment of endocrine disruptors in wildlife and humans –scientific criteria for regulatory decision making in the EU -- risk factor for human fertility S3-2: Exposure to ED in humans: assessing biomarkers of effect S3-3: The screening of everyday life chemicals for endocrine activity – data interpretation and impact S33-4: Species difference in susceptibility to inhibition of fetal testis steroidogenesis
  15. 15. 10. Sept. Symposium 3 : Reproductive toxicity –endocrine mechanisms S3-1: Identification and assessment of endocrine disruptors in wildlife and humans –scientific criteria for regulatory decision making in the EU S3-2: Exposure to ED in humans: assessing biomarkers of effect S3-3: The screening of everyday life chemicals for endocrine activity – data interpretation and impact S33-4: Species differece in susceptibility to inhibition of fetal testis steroidogenesis
  16. 16. 10. Sept. Symposium 4 : Reproductive toxicity- epigenetics S4-1: System and genome wide adaptation of the epigenome to gestational stress  Hypothesis that system wide DNA methylation changes early in life in response to social stress occur in both animal and humans.  “Adaptive genomic” mechanism that prepares life-long genome programming to the anticipated life long environment based on stress signal received during gestation and early life.  Glucocorticoids: act as “integrators” that translate the social stress signals during gestation to genome wide methylation changes across multiple systems
  17. 17. 10. Sept. S4-2: Sex-specific transcriptional and epigenetic signatures associated with peripheral leptin-resitance  Non-communicable disease(NCDs) : 60% of worldwide deaths  Next decade : 17% increase  Fundamental misconception : Obesity, NCDs  Paradime shift : DOHaD  Early nutritional events: influence on later life health through epigenetic process  Evidence : maternal obesity and Type 2 diabetes at conception, gestation & lactation promote development of obesity and diabetes of offspring in their adulthood  2 generation mice model : Obese and diabetic with CD during periconceptional/ gestational/lactation period led to sex specific shift form susceptibility to resistance to HFD in female offspring only  Sex specific liver disease risk : unsuspected role of Lepr gene in peripheral sex specific leptin resistance
  18. 18. 10. Sept. S4-3: Diabetic embryopathy : the role of epigenetics  Epigenetic information : silencing or activation of genes heritable change in gene expression without changes in DNA sequence  Hyperglycemia affects epigenome  Oxidative stress/ apoptosis/hypoxia 에 반응하는 유전자의 epigenetic changes eq. NRF2-mediated oxidative stress response pathway Endoplasmic reticulum pathway  Maternal diabetes seems to cause long lasting changes in the embryonic epigenome by different mechanism. These changes might be responsible to the diabetes induced teratogenicity
  19. 19. 11. Sept. Symposium 5 : Regulatory acceptance of alternative/in vitro methods S5-1: Bottlenecks for the implementation of alternative methods in regulatory reproductive and developmental toxicity testing : Alternative method in regulatory method not easily accepted whole embryo culture/zebrafish embryotoxicity/ embryonic stem cell S5-2: Validation- an intrinsic part of safety assessment science : reliability / relevance S5-3: Science for or science based regulation: is there a missing link? : Yes
  20. 20. Abstract Characterization of phosphatidylethanol blood concentrations for screening alcohol consumption in early pregnancy Termination rate in Korean pregnant women who received counseling in a teratology information service in the first trimester of pregnancy due to exposure
  21. 21. Abstract Effects of ß-carotene in cultured mouse embryos exposed to nicotine Cunmei Lin, Sang-Yoon Nam Chung-buk natioanal University Evaluation of human embryonic stem cell to screen developmental Toxicants EM Jung Chung-buk natioanal University
  22. 22. Diet and Autism spectrum disorders(ASD) Yasmin H. Departmenet of Human nutrition, The University of Alabama, USA No clear etiology or cure for ASD Nutritional factor may play a role in Tx of ASD restriction of food allergens, probiotics, ketogenic diet, yeast free diet, gluten and casein free diet Methods: literature review ; 3 types of diet casein free –gluten free diet(GFCF), ketogenic and antioxidant diet Results: GFCF diet show the most promise of efficacy however, inconvenience and limitation Conclusion : GFCF requires further safety studies.
  23. 23. Synergistic use of ex vivo and in vitro placenta model systems to study various aspects of nanomaterial behavior at the placental barrier Tina BT. NP(fluorescent polystyrene) is increasing production. Major potential for the development of novel thearapeutic strategies to treat specifically either the mother or the developing fetus. So issue is for trans-placental transfer or placental effects NP 50, 80, 240, 500nm Ex vivo human placental perfusion system 2 novel placenta system(for mechanistic study): a perfused transwell co-culture system a 3D placental microsphere model 240nm : taken by placenta cross placental barrier without affecting the viability of placental explant Established systems for mechanistic study
  24. 24.  Biopharmaceuticals & DART  Nanoparticles  2nd species of developmental toxicity  Endocrine disruptor  Epigenetics  Regulatory acceptance of alternative/in vitro methods Summary
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